RS50662B - NEW SYNTHESIS PROCEDURE AND NEW CRYSTAL FORM OF AGLOMELATIN AS AND PHARMACEUTICAL MIXTURES CONTAINING IT - Google Patents

Abstract

Process for the industrial synthesis of a compound of formula (I) subjected to reaction of 7-methoxy-1-tetralone of formula (III): with cyanosacetic acid of formula (IV): under conditions of elimination of formed water, in the presence of a catalytic amount of a compound of formula (V): u to which R and R ', the same or different, each represent a linear or branched (C3-C10) alkyl group, unsubstituted or substituted aryl group, or unsubstituted or substituted linear or branched (C1-C6) arylalkyl group, to form, after of filtration and washing with a basic solution, (7-methoxy-3,4-dihydro-1-naphthalenyl) acetonitrile of formula (VI): the compound of formula (VI) is reacted with a hydrogenation catalyst in the presence of an allyl derivative to give the compound of formula (VII) ): which is then subjected to reduction with hydrogen in the presence of the presence of Raney nickel in an ammonia-ethanol environment and then converted to the salt by hydrochloric acid to give the compound of formula (VIII): is then subjected to sodium acetate then acetic anhydride to give the compound of formula (I) which is isolated as a solid, with the understanding that: - aryl means a phenyl, naphthyl or biphenyl group, - the term "substituted" refers to the formulas "aryl" and "arylalkyl" signifying that the aromatic moiety of these groups may be substituted by 1 to 3 of the same or different groups selected from linear or branched (C1-C6) alkyl, hydroxy and linear or branched (C1-C6) alkoxy , - "allyl derivative" means a complete molecule containing 3 to 10 carbon atoms and may have another 1 to 5 oxygen atoms and, containing at least one motive -CH2-CH = CH2. The application contains 18 more claims.

Description

NEW SYNTHESIS PROCEDURE AND

NEW CRYSTAL SHAPE

AGGLOMELATIN AS WELL

PHARMACEUTICAL MIXTURES THAT CONTAIN IT

CONTENTS

This invention relates to the process of industrial synthesis of agomelatine or N-[2-(7-methoxy-1-naphthyl)ethyl]acetamide of formula (I):

This invention also relates to the crystalline form II of agomelatine, the method of its production, as well as to pharmaceutical mixtures containing it.

Agomelatine, or W-[2-(7-methoxy-1-naphthyl)ethyl]acetamide, has beneficial pharmacological properties.

It exhibits the effect of a double peculiarity, that on the one hand it is an agonist on the receptors of the melatoninergic system, and on the other hand it is an antagonist of the 5-HT2C receptor. These properties give it activity in the central nervous system and, more precisely, in the treatment of general depression, seasonal depression, sleep disorders, cardiovascular pathologies, digestive system pathologies, insomnia and fatigue as a result of time difference, appetite disorders and obesity.

Agomelatine, its production and its use for therapeutic purposes are described in European patent EP 0 447 285.

In order to evaluate the pharmaceutical benefit of this compound, it is also important that it can be used in the process of industrial synthesis, which is easily set up in an industrial process, which produces agomelatine in good yield and excellent purity.

Also important is the possibility of using agomelatine in the form of a well-defined crystalline form, perfectly reproducible and which exhibits useful properties in terms of filtration and formulation facilitation.

Patent EP0 447 285 describes an eight-step approach to agomelatine, starting from 7-methoxy-1-tetralone with an average yield below 30%.

This process involves the action of ethyl bromoacetate, followed by aromatization and saponification to give the corresponding acid, which is then transformed into acetamide, then dehydrated to give (7-methoxy-1-naphthyl)acetonitrile, followed by reduction and then condensation of acetyl chloride.

More precisely, the approach to (7-methoxy-1-naphthyl)acetonitrile presupposes six reaction stages and, switching to the industrial process, the difficulties of this process were quickly noticed mainly due to the reproducibility problems of the first stage, which consists of the action of ethyl bromoacetate on 7-methoxy-tetralone according to the Reformatsk reaction, which produces ethyl (7-methoxy-3,4-dihydro-1(2W)-naphthalenylidene)ethanoate.

In addition, the subsequent aromatization step of ethyl (7-methoxy-3,4-dihydro-1(2H)-naphtha!enylidene)ethanoate was often incomplete and produced, after saponification, a product mixture that was difficult to purify.

The literature describes a three-step approach to (7-methoxy-1-natyl)acetonitrile, starting with 7-methoxy-1-tetralone under the action of LiCH2CN, followed by dehydrogenation to DDQ (2,3-dichloro-5,6-dicyano-1,4-benzoquinone) and, finally, dehydration in acidic media (Svnthetic Communication, 2001, 31(4), 621-629). Each time the total yield is average (76%) and, above all, the DDQ used in the dehydrogenation reaction as well as the benzene reflux which is necessary in the third stage do not correspond to Industrial conditions in terms of costs and the natural environment.

The applicant today offers a new process of industrial synthesis which obtains, in a reproducible manner and without the need for painstaking purification, agomelatine with a purity compatible with its use as an active pharmaceutical principle.

An alternative to the difficulties encountered with the process, which is described in patent EP 0 447 285, was achieved by direct condensation of the cyano derivative on 7-methoxy-1-tetralone.

It is necessary, besides, that the compound, obtained by condensation, is then simply subjected to aromatization in order to obtain (7-methoxy-1-naphthyl)acetonitrile without the need for drastic conditions and allowing the use of reagents compatible with the requirements of industrial cost and natural environment.

It turned out that (7-methoxy-3,4-dihydro-1-naphthalenyl)acetonitrile is an ideal synthetic intermediate that meets the needs of direct synthesis, which starts with 7-methoxy-1-tetralone and provides an excellent substrate for the aromatization step.

Direct condensations of tetralone with acetonitrile or acetonitrile derivatives have been described in the literature. In particular, US Patent 3,992,403 describes the condensation of cyanomethylphosphonate on 6-fluoro-1-tetralone and, US Patent 3,931,188 describes the condensation of acetonitrile on tetralone, which produces a cyano intermediate, which directly enters the next reaction.

Applied to 7-methoxy-1-tetralone, the condensation of acetonitrile produces a mixture of isomers, the major "exo" and the minor "endo", as per Figure 1:

that mixture requires subsequent conditions of drastic aromatization, which are not compatible with industrial requirements in terms of continuing agomelatine synthesis.

The applicant today offers a new process of industrial synthesis, which allows obtaining (7-methoxy-1-naphthyl)acetonitrile in a reproducible way and without the need for painstaking purification, in two stages only by starting from 7-methoxy-tetraion, using as an intermediate of synthesis, (7-methoxy-3,4-dihydro-1-naphthalenyl)acetonitrile freed from the "exo" impurity of the formula (II):

which cannot undergo a subsequent aromatization reaction under operating conditions compatible with industrial requirements in order to proceed with the synthesis of agomelatine.

More precisely, this invention relates to the process of industrial synthesis of compounds of formula (I):

which is described by reacting 7-methoxy-1-tetralone of formula (III): with cyanoacetic acid of formula (IV): under conditions of elimination of formed water, in the presence of a catalytic amount of a compound of formula (V): in which R and R', the same or different, each represent a linear or branched (C3-C10) alkyl group, an unsubstituted or substituted aryl group, or an unsubstituted or substituted linear or branched (Ci-Ce) arylalkyl group, to give, after filtration and washing with base solution, (7-methoxy-3,4-dihydro-1-naphthalenyl)acetonitrile of formula (VI): the compound of formula (VI) is reacted with a hydrogenation catalyst in the presence of an allyl derivative to give the compound of formula (VII): which is then subjected to reduction with hydrogen in the presence of Raney nickel in an ammonia-ethanol medium, and then is translated into salt using hydrochloric acid in order to obtained a compound of formula (VIII):

which is then subjected to the action of sodium acetate and then acetic anhydride to obtain the compound of formula (I) which is isolated as a solid,

with the understanding that:

aryl means a phenyl, naphthyl or biphenyl group,

the term "substituted" refers to the formulas "aryl" and "arylalkyl" indicating that the aromatic part of these groups can be substituted with 1 to 3 of the same or different groups, selected from linear or branched (Ci-Ce) alkyl, hydroxy and linear or branched (Ci-Ce) alkoxy,

"allylic derivative" means a complete molecule containing 3 to 10 carbon atoms and may have 1 to 5 more oxygen atoms and, containing at least one motif-CH2-CH=CH2.

More precisely, in the reaction of the transformation of the compound of formula (III) into the compound of formula (VI), the water formed is eliminated by distillation. Preferably, a reaction solvent is used which has a boiling point higher than or equal to that of water, and even better, which forms an azeotrope with water, such as, for example, xylene, toluene, anisole, ethylbenzene, tetrachloroethylene, cyclohexene, or mesitylene.

In the best way, the reaction of transformation of the compound of formula (III) into the compound of formula (VI) is carried out under the reflux of toluene or xylene, and even better, under the reflux of toluene.

Advantageously, in the reaction of the transformation of the compound of formula (III) into the compound of formula (VI), one of the groups R or R' of the used catalyst represents a linear or branched (C3-C10) alkyl group, and the other represents an aryl or arylalkyl group. More precisely, the preferred catalyst is the one with the formula (Va):

in which R' represents a phenyl group, which is unsubstituted or substituted by one or more linear or branched (Ci-C8) alkyl groups, n is 0 or 1, and R represents a linear (C3-C10) alkyl group.

Very advantageously, R' represents an unsubstituted or substituted phenyl group, more specifically an unsubstituted phenyl group.

The Raje group is preferably a hexyl group.

Advantageously, n is 1.

The catalyst, which is preferably used in the reaction of the transformation of the compound of formula (III) into the compound of formula (VI), and which is in accordance with the process of the invention, is benzylammonium heptanoate of formula (IX):

Advantageously, the compound of formula (VI) is obtained after filtration and washing with an organic base solution or mineral, such as: NaOH, KOH, Ca(OH) 2 , Sr(OH) 2 or NH 4 OH, and even better, with sodium hydroxide solution.

Preferably, the transformation reaction of the compound of formula (VI) to the compound of formula (VII) is carried out in refluxing toluene or xylene, and even better, in refluxing toluene.

The catalyst, which is preferably used in the reaction of the transformation of the compound of formula (VI) into the compound of formula (VII), is a catalyst in the form of an oxide or on a support, such as, for example, palladium, platinum, nickel, Al 2 O 3 a, more precisely, palladium. Advantageously, palladium on carbon will be used, more precisely, palladium on carbon from 1 to 20% and even more precisely, up to 5% or 10%. Preferably, palladium on carbon will be used in catalytic amounts, more specifically, in amounts between 1 to 10% by weight of the catalyst relative to the weight of the substrate, and even better, 5%.

The hydrogen acceptor used in the transformation reaction of the compound of formula (VI) into the compound of formula (VII) is preferably an allyl derivative and, in particular, an allyl acrylate or an allyl glycidyl ether. The allyl acrylate preferred in the process according to the invention is allyl methacrylate.

Advantageously, the reaction of transforming the compound of formula (VII) into the compound of formula (VIII), which is in accordance with the process of the invention, is carried out between 20 and 40°C and, more preferably, between 30 and 40°C, and even more preferably, at 40°C.

Advantageously, the transformation reaction of the compound of formula (VIII) into the compound of formula (I) is carried out in an alcoholic medium and, more precisely, in an ethanolic medium.

This procedure is particularly useful for the following reasons:

• enables obtaining, by an industrial process, the "endo" compound of formula (VI) in an exclusive way. This result is quite surprising when considering the literature related to that type of reaction, which most often ensures the obtaining of "exo" / "endo" mixtures (Tetrahedron, 1966, 22, 3021-3026). This result derives from the use of the compound of formula (V) as a reaction catalyst in place of and instead of ammonium acetate, which is usually used in these reactions (Buli. Soc. Chim. Fr., 1949, 884-890). • the rate of achieved transformation of the compound of formula (III) into the compound of formula (VI) is very high, over 97%, compared to the one obtained by using acetic acid, with which the rate does not exceed 75%. • the use of a hydrogenation catalyst in the presence of an allyl derivative and, more precisely, an allyl methacrylate, for the transformation of a compound of formula (VI) into a compound of formula (VII) is quite compatible with industrial cost and environmental requirements, as opposed to quinones currently used. • allows, in addition, to obtain by industrial process the compound of formula (VII) in an exclusive way, especially free of the reduction product corresponding to formula (X): • finally, it was observed that the transformation rates of the compound of formula (VI) into the compound of formula (VII) were increased, more than 90%.

■ the hydrogenation of the compound of formula (VII) in the presence of Ranev's nickel in an ammonia-ethanol medium was described (J. Med. Chem., 1994, 37(20), 3231-3239), but difficult conditions are necessary for the transfer to the industrial process: the reaction takes place at 60°C for 15 hours and the final yield is less than 90%.

In fact, the main disadvantage of this reaction is the simultaneous formation of "bis" derivatives of formula (XI):

and, the difficulty is mastering the course of formation of this impurity. The procedure pointed out by the applicant enables the preparation of compounds of formula (VIII) with an amount of bis impurity below 4%, with performance conditions compatible with industrial requirements since the reaction takes place between 30 and

40°C to produce yields greater than 90% and chemical purity greater than 99.5%. • the stage of conversion to amide takes place in an alcoholic environment, more precisely, ethanolic, which enables very easy isolation of the compound of formula (I) with a single quantitative yield. This result is completely surprising because this type of reaction is hardly compatible with a solvent for which competitive consumption of acetic anhydride is expected.

The compound of formula (VI) obtained according to the process of the invention is new and useful as an intermediate in the synthesis of agomelatine in which it undergoes an aromatization reaction, followed by a reduction reaction, then coupling with acetic anhydride.

The invention also relates to the crystalline II form of agomelatine obtained in accordance with the previously described procedure. Finally, it is important that it is possible to obtain a crystal form that is well defined and perfectly reproducible.

Previous application EP0447285 and Yous et al. (Journal of Medicinal Chemistry, 1992, 35 (8), 1484-1486) provide access to agomelatine in a particular crystalline form described in Tinant et al. (Acta Cryst., 1994, C50, 907-910).

The applicant now outlines a process for obtaining agomelatine in a well-defined crystalline form, perfectly reproducible and exhibiting truly useful properties in terms of filtration and ease of formulation.

More specifically, this invention relates to the crystalline form II of agomelatine, which is characterized by the following parameters, which were obtained starting from the powder pattern performed on a high-resolution D8 Bruker AXS diffractometer with an angular range of 3°-90° at 28, one step of 0.01° and 30 s per step:

• crystalline okce monoclinic,

• loop parameters: a = 20.0903 A, b = 9.3194 A, c = 15.4796 A, 8 = 108.667°

• spacing group : P2,/ r\

• number of molecules in the cell: 8

• volume of the volume: Vokca= 2746.742 A<3>

• density: d = 1.13 g/cm<3>.

Obtaining this crystalline form has the advantage of enabling particularly fast and efficient filtration, as well as the production of pharmaceutical formulations that have a constant and reproducible composition, which are particularly advantageous when these formulations are intended for oral administration.

The form thus obtained is stable enough to allow its prolonged storage without special conditions of temperature, light, humidity or oxygen flow.

Pharmacological examination of the form obtained in this way shows an important activity on the central nervous system, as well as on microcirculation, and this allows establishing its use in the treatment of stress, sleep disorders, fears, general depression, seasonal depression, cardiovascular pathologies, digestive system pathologies, insomnia and fatigue as a result of time difference, schizophrenia, panic attacks, melancholy, appetite disorders, obesity, insomnia, pain, psychotic disorders, epilepsy, diabetes, Parkinson's disease, senile dementia, various disorders associated with normal or pathological aging, migraines, memory loss, Alzheimer's disease, as well as for cerebral circulation disorders. In another domain of activity, it seems that in treatment, form II agomelatine can be used in sexual dysfunctions, as it has the properties of ovulation inhibitor, immunomodulator and as it is suitable to be used in the treatment of cancer.

The crystalline II form of agomelatine will have the advantage of being used in the treatment of general depression, seasonal depression, sleep disorders, cardiovascular pathologies, digestive system pathologies, insomnia and fatigue as a result of time difference, appetite disorders and obesity.

The invention also relates to pharmaceutical mixtures containing, as an active principle, the crystalline II form of agomelatine with one or more inert bases, which are non-toxic and suitable. Of the pharmaceutical compositions according to the invention, those suitable for administration can be mentioned in particular: oral, parenteral (intravenous or subcutaneous), nasal, simple pills or dragees, granules, sublingual pills, gelatin capsules, tablets, suppositories, creams, ointments, skin gels, injectable preparations, oral suspensions and chewing pastes.

The dosage used is adjustable according to the nature and severity of the disease, the route of administration, as well as the age and weight of the patient. This dosage varies from 0.1 mg to 1 g once or more times a day.

Example: N-[2-(7-methoxy-1-naphthyl)ethyl]acetamide

Step A: (7-methoxy-3,4-dihydro-1-naphthalene)acetonitrile

In a 670 I reactor, 85.0 kg of 7-methoxy-1-tetralone, 60.3 kg of cyanoacetic acid and 15.6 kg of heptanoic acid were introduced into toluene, in the presence of 12.7 kg of benzylamine. The reaction medium was brought to reflux. When the initial substrate disappears completely, the solution is cooled and filtered. The obtained precipitate is washed with toluene, and then the obtained filtrate is washed with 2N soda solution, then with water until the reaction is neutral. After evaporation of the solvent, the resulting solid was recrystallized from ethanol/water (80/20) to give the title product in 90% yield and 99% high chemical purity.

Melting point: 48-50°C

Step B: (7-methoxy-1-naphthyl)acetonitrile

12.6 kg of 5% palladium on carbon was introduced into the 670 I reactor in toluene and brought to reflux, then 96.1 kg of (7-methoxy-3,4-dihydro-1-naphthalenyl)acetonitrile in solution in toluene was added, as well as 63.7 kg of allyl methacrylate. The reaction is continued at reflux and then subjected to volatile phase chromatography. When the initial substrate disappears completely, the reaction medium is cooled to room temperature and then filtered. After evaporation of the toluene, the resulting solid residue was recrystallized from ethanol/water (80/20) to give the title product in 91% yield and 99% high chemical purity.

Melting point: 83°C

Step C: 2-(7-methoxy-1-naphthyl)ethanamine, hydrochloride

80.0 kg of the compound obtained in step B and 24.0 kg of Ranev's nickel in ethanol and 170 L of ammonia were introduced into the 1100 L reactor. The reaction medium was shaken and subjected to a hydrogen pressure of 30 bar, and then brought to 40°C. When the starting substrate has completely disappeared, the solvent is evaporated and the resulting residue is redissolved in ethyl acetate and 41.5 L of 11N hydrochloric acid solution is added. After filtration, the resulting precipitate was washed with ethyl acetate, then dried in an oven to give the title product in 95.3% yield and greater than 99.5% chemical purity.

Melting point: 243°C

Step D: N-[2-(7-methoxy-1-naphthyl)ethyl]acetamide

173 kg of the compound obtained in step C and 66 kg of sodium acetate in ethanol were introduced into the 1600 I reactor. The reaction medium was shaken and then 79 kg of acetic anhydride was added, the reaction medium was brought to reflux and 600 L of water was added. The reaction was allowed to return to ambient t and the resulting precipitate was filtered, washed with ethanol/water 35/65 to give the title product in 92.5% yield and greater than 99% chemical purity.

Melting point: 108°C

Primer 2: N-[2-{7-methoxy-1-naphthyl)ethyl]acetamide

Step A :( 7- methoxy- 3, 4- dihydro- 1- naphthaleneH) acetonitrile

85.0 kg of 7-methoxy-1-tetralone, 60.3 kg of cyanoacetic acid and 15.6 kg of heptanoic acid in toluene were introduced into the 670 I reactor, in the presence of 11.0 kg of aniline. The reaction medium was brought to reflux. When the initial substrate has completely disappeared, the solution is cooled and filtered. The obtained precipitate is washed with toluene, and then the obtained filtrate is washed with 2N soda solution, then with water until the reaction is neutral. After evaporation of the solvent, the resulting solid was recrystallized from ethanol/water (80/20) to give the title product in 87% yield and 99% high chemical purity.

Melting point: 48- 50°C

Step B: (7-Methoxy-1-naphthyl)acetonitrile

Proceed as in step B of Example 1.

Melting point: 83°C

Step C: 2-(7-Methoxy-1-Naphthyl)Ethanamlin, Hydrochloride

Proceed as in step C of Example 1.

Melting point: 243°C

Step D: N-f2-(7-Methoxy-1-naphthyl)ethynacetamld

Proceed as in step D of Example 1.

Melting point: 108°C

Primer 3: Crystal form II of N-[2-(7-methoxy-1-naphthyl)ethyl]acetamide

Data recording was performed on a D8 Bruker AXS high-resolution diffractometer with the following parameters: angular range 3°-90° at 28, one step of 0.01° and 30 s per step. The N-[2-(7-methoxy-1-naphthyl)ethyl]acetamide powder obtained in Example 1 was placed on a transfer mount. The X-ray source is a bakama tube (XCuKai= 1.54056 A). The machine contains a monochromator inside (Ge(111) crystal) and a solid energy decomposition detector (MXP-D1, Moxtec-SEPH).

The compound is perfectly crystallized: the width of the stripes at medium height is of the order of 0.07° at 28.

Also, the following parameters were determined:

• crystalline okce monoclinic,

• loop parameters: a = 20.0903 A, b = 9.3194 A, c = 15.4796 A, 8 = 108.667°

• spacing group :P2- j/ n

• number of molecules in the cell: 8

• volume of the volume: Vokca= 2746.742 A<3>

• density: d = 1.13 g/cm<3>.

Example 4: Pharmaceutical composition

Formula for making 1000 pills of 25 mg dose:

Example: Pharmaceutical mixture

Formula for making 1000 pills of 25 mg dose:

Claims (19)

1. Process of industrial synthesis of compounds of formula (I) indicated by the fact that it undergoes the reaction of 7-methoxy-1-tetralone formula (III): with cyanoacetic acid of formula (IV): under conditions of elimination of formed water, in the presence of a catalytic amount of the compound of formula (V): wherein R and R', the same or different, each represent a linear or branched (C3-C10) alkyl group, an unsubstituted or substituted aryl group, or an unsubstituted or substituted linear or branched (C1-C8) arylalkyl group, to obtain, after filtration and washing with base solution, (7-methoxy-3,4-dihydro-1-naphthalenyl)acetonitrile of formula (VI): A compound of formula (VI) is reacted with a hydrogenation catalyst in the presence of an allylic derivative to give a compound of formula (VII): which then undergoes reduction with hydrogen in in the presence of Raney's nickel in an ammonia-ethanol medium, and then salted with hydrochloric acid to give the compound of formula (VIII): which is then subjected to the action of sodium acetate and then acetic anhydride to give the compound of formula (I) which is isolated as a solid, with the understanding that: aryl means a phenyl, naphthyl or biphenyl group, the term "substituted" refers to the formulas "aryl" and "arylalkyl" indicating that the aromatic portion of these groups may be substituted with 1 to 3 of the same or different groups selected from linear or branched (C-, -C6) alkyl, hydroxy and linear or branched (CVC^) alkoxy, "allyl derivative" means a complete molecule containing 3 to 10 carbon atoms and may have 1 to 5 more oxygen atoms and, containing at least one motif -CH2-CH=CH2. 2. The method of synthesis of the compound of formula (I), as in patent claim 1, indicated by the fact that the reaction of transformation of the compound of formula (III) into the compound of formula (VI) takes place in toluene reflux. 3. Method of synthesis of compounds of formula (I), as in patent claim 1, indicated by the fact that R represents a hexyl group. 4. Process for the synthesis of compounds of formula (I), as in claim 1, characterized in that R' represents a benzyl group. 5. The method of synthesis of the compound of formula (I), as in patent claim 1, indicated by the fact that the catalyst used in the reaction of the transformation of the compound of formula (III) into the compound of formula (VI) is the compound of formula (Va): in which R' represents a phenyl group, which is unsubstituted or substituted by one or more linear or branched (CVCe) alkyl groups, n is 0 or 1, and R represents a linear (C3-C10) alkyl group. 6. The method of synthesis of the compound of formula (I), as in patent claim 1, indicated where the catalyst is used for the reaction of the transformation of the compound of formula (III) into the compound of formula (VI) benzylammonium heptanoate of formula (IX): 7. The method of synthesis of the compound of formula (I), as in patent claim 1, indicated by the fact that the reaction of transformation of the compound of formula (VI) into the compound of formula (VII) takes place in toluene reflux. 8. The method of synthesis of the compound of formula (I), as in patent claim 1, characterized by the fact that the hydrogenation catalyst used in the reaction of the transformation of the compound of formula (VI) into the compound of formula (VII) is palladium. 9. The method of synthesis of the compound of formula (I), as in patent claim 1, characterized by the fact that the hydrogenation catalyst used in the reaction of the transformation of the compound of formula (VI) into the compound of formula (VII) is palladium on carbon of 5%. 10. The method of synthesis of compounds of formula (I), as in patent claim 1, indicated by the fact that the amount of hydrogenation catalyst used in the reaction of transformation of compounds of formula (VI) into compounds of formula (VII) is 5% by weight of the catalyst based on the weight of the substrate. 11. The method of synthesis of the compound of formula (I), as in patent claim 1, indicated by the fact that the reaction of transformation of the compound of formula (VII) into the compound of formula (VIII) takes place at 40°C. 12. The method of synthesis of the compound of formula (I), as in patent claim 1, characterized by the fact that the reaction of transformation of the compound of formula (Villi) into the compound of formula (I) takes place in ethanol. 13. A process for the synthesis of agomelatine, starting from a compound of formula (VI), characterized in that the compound of formula (VI) is obtained by a synthetic process according to any of claims 1 to 6, which is subjected to a reaction with a hydrogenation catalyst in the presence of an allyl derivative to obtain a compound of formula (VII): which is then subjected to reduction with hydrogen in the presence of Raney nickel in an ammonia-ethanol medium, and then converted to a salt using hydrochloric acid to give a compound of formula (VIII): which is then treated with sodium acetate followed by acetic anhydride to give the compound of formula (I) which is isolated as a solid. 14. A process for the synthesis of agomelatine, starting from a compound of formula (VII), characterized in that the compound of formula (VII) is obtained by a synthetic process according to any one of claims 1 to 6 and 7 to 10, which is subjected to reduction with hydrogen in the presence of Raney nickel in an ethanolic ammonia medium, and then converted into a salt using hydrochloric acid to obtain a compound of formula (VIII): which is then treated with sodium acetate followed by acetic anhydride to give the compound of formula (I) which is isolated as a solid. 15. The method of agomelatine synthesis, starting from the compound of formula (VIII), characterized in that the compound of formula (VIII) is obtained by a synthetic process that is in accordance with any of patent claims 1 to 6 and 7 to 11, which is subjected to the action of sodium acetate, then acetic anhydride in order to obtain the compound of formula (I), which is isolated in the form of a solid mass. 16, Crystal II form of agomelatine of formula (I): indicated by the following parameters, which were obtained starting from the powder diagram performed on a high-resolution D8 Bruker AXS diffractometer with an angular range of 3°-90° at 28, one step of 0.01° and 30 s per step: • crystal occa monoclinic, • occa parameters: a = 20.0903 Å, b = 9.3194 Å, c = 15.4796 A,6= 108.667° • distance group: P2i/n • number of molecules in the eye: 8 • volume of the eye: V^««= 2746.742 A<3>• density: d = 1.13 g/cm<3>. 17. Pharmaceutical mixtures contain as an active principle the crystalline II form of agomelatine in accordance with patent claim 16, in combination with one or more inert vehicles, which are non-toxic and pharmaceutically acceptable. 18. Pharmaceutical mixtures, as in patent claim 17, which are used for the production of drugs for the treatment of disorders of the melatoninergic system. 19. Pharmaceutical mixtures, as in patent claim 17, which are used for the production of drugs for the treatment of sleep disorders, stress, fears, seasonal depression or general depression, cardiovascular pathologies, pathologies of the digestive system, insomnia and fatigue as a result of time difference, schizophrenia, panic attacks, melancholia, appetite disorders, obesity, insomnia, psychotic disorders, epilepsy, diabetes, Parkinson's disease, senile dementia, various disorders associated with normal or pathological aging, migraine, memory loss, Alzheimer's disease, cerebral circulation disorders, as well as in sexual dysfunctions, as ovulation inhibitors, immunomodulators and in the treatment of cancer.